Therapeutic treatment with 1,2-dihydro-1,2,4-benzotriazine derivatives



United States Patent US. Cl. 424-249 6 Claims ABSTRACT OF THE DISCLOSURE This invention is directed to method of alleviating inflammation, edema, pain, fever and swelling of the joints with 1,2-dihydro-1,2,4-benzotriazine derivatives.

This application is a division of our copending application Ser. No. 405,592, filed Oct. 21, 1964, now Patent No. 3,349,088.

The present invention relates to therapeutically valuable compounds of the general formula 3,482,024 Patented Dec. 2, 1969 ice wherein X and Y have the above mentioned signification, with reducing agents and isolating the reduction product in the form of a crystalline salt with acids or as an acyl derivative. The l,2-.malonyl derivatives give salts with bases.

' The above described compounds exert when perorally or parenterally administered either as such or in the form of their salts good antiphlogistic effects and have also analgetic and antipyretic properties. The compounds disclosed herein are useful for alleviating rheumatic and allergic diseases and symptoms of inflammation, edema, pain, fever, and swelling of the joints by administering to the patients having such symptoms 50-1200 mg. per day of said compounds.

. The compounds of Formula II can be reduced by catalytic hydrogenation or by means of meta s having reducing properties (Sn, Zn, Fe etc.) or with salts of them (SnCI FeCl etc.). Reduction and isolation of the desired product is preferably carried out in an inert atmosphere such as N or H The following table shows a comparison between the compounds of this invention and the well-known antirheumatics phenylbutazone and sodium salicylate, in view of their inhibiting effect on the rat paw kaolin edema. On this model all the well-known antirheumatic remedies exhibit antiphlogistic properties, even on peroral administration; see Arzneimittel-Forschung 12, 1160 (1962).

Perorally ED given as (dose for Substituents of formula I salt of 50% inhibi- D1150 (dose DL50/ED5U acid or tion of for 50% (therapeutic X Y Z Z2 base, resp. edema) letality) index Compound No.2

M0 533 (7)01 N Hz H H H01 145 720 5 M0 780 H N(OH )2 H H H01 300 ca 1, 250 ea. 4 M0 817 (7)01 N(CH3)2 H H H01 90 ca. 450 ca. 5 M0 828 (7 H H HCl 115 910 8 M0 815 ca. 220 ca. 800 ca. 4 Mi 73A ca. 70 440 ca. 6. 3 M0 855". 09.. 225 3, 500 15 M0 874 120 780 6. 5 M0 888 90 610 6.8 M1 57 70 491 7 M185 ca. 100 1, 350 ca. 13. 5 Phenylbutazone 170 770 4 Sodium salicylate... 600 1, 600 2. 7

l X ILI wherein X and X are identical or different members of the group consisting of hydrogen, halogen, lower alkyl, free and substituted amino groups, free, alkylated and acylated hydroxy groups; Y is a member of a group consisting of lower alkyl, aryl, free and substituted amino groups and free, alkylated and acylated hydroxy groups, and Z and Z are identical or different members of the group consisting of hydrogen and acyl radicals where both Z together may represent the diacyl biradical of a dibasic acid which may be substituted by lower alkyl, lower alkenyl, cycloalkyl, aryl and hydrocarbon radicals, eventually substituted by a member of the group including free and substituted amino radicals and free, alkylated and acylated hydroxy radicals.

The novel compounds of the invention are preferably prepared by treating a 1,2,4-benzotriazine-l-oxide of the general formula The last column of this table shows that the therapeutic indices in the kaolin edema test for most of the compounds of this invention, are higher than those of phenylbutazone or sodium salicylate.

The following table shows that compounds of this invention on peroral administration have a higher antipyretic effect against the rat yeast fever and a stronger analgesic effect (phenylquinone test of Siegmund) than phenylbutazone or sodium salicylate.

lntraperitoneal injection of a 0.025% phenylquinone solution containing 5% alcohol (0.1 ml. per 10 g. rat) 30 minutes after administration of the substance to examine. The typical pain-induced wreathing was observled on 5 animals during 20 minutes and compared with non treated amma s.

Intramuscular injection of a 15% yeast suspension (1 ml./ mg. body weight) 3 EXAMPLE 1 3-amino-7-chloro(1,2-dihydro-1,2,4-benzotriazine) (Mo 5 3 3 7 g. of the compound corresponding to Formula II 5 3-dimethylamino-( 1,2-dihydro-1,2,4-benzotriazine) (Mo 7 80) 7 g. of the compound corresponding to Formula II (X=H, Y=N(CH are, as described in Example 1, reduced with tin and hydrochloric acid. After cooling the reaction product crystallizes as a tin double salt. This salt is suspended in 50 parts of 1 N hydrochloric acid and treated at 80 C. with H S. Evaporation of the filtered solution yields hexagonal prisms of the monochlorhydrate. M.P. 205-207 C.

Analysis.-C H N Cl /2H O (221.7). Calcd.: 48.8%; H, 6.33%. Found: C, 49.3%; H, 6.3%.

EXAMPLE 3 3-propoxy-(1,2-dihydro-1,2,4-benzotriazine) The starting material having the structure II (Y=H, Y=OC H,) can be obtained by heating 3-chloro-1,2,4- benzotriazine-l-oxide with the equivalent amount of sodium propylate in n-propanol (M.P. 90 92 C.). The hydrogenation is carried out with zinc powder and ammonia by heating a stirred mixture of 6.4 g. of the starting material with 6.4 g. of zinc powder in 260 ml. of alcohol and 130 ml. of concentrated ammonia on a water bath while introducing gaseous ammonia. As soon as the orange color of the solution disappears, the filtered alcoholic solution is evaporated under N The residue is extracted with peroxyde-free ether, and 3n alcoholic hydrochloric acid is added to the extract. The resulting hydrochoride has a melting point of 110-111 C.

Analysis.C H N OCl (227.7). Calcd.: C, 52.73%; H, 6.2%; Cl, 15.57%. Found: C, 52.83%; H, 6.36%;

EXAMPLE 4 1-acetyl-3-propoxy-(1,Z-dihydro-1,2,4-benzotriazine) 2 g. of the starting material of Formula H (X=H, Y=OC H-,) are dissolved in a mixture of ml. glacial acetic acid and 2 g. acetic anhydride. The reduction is carried out with hydrogen in the presence of 200 mg. Raney-nickel. The filtered solution is heated to 90 C. and after dilution with 250 ml. of Water the product melts at 144-145 C.

Analysis.C H N O (233.3). Calcd.: C,61.77%; H, 6.48%; N, 18.0%. Found: C, 61.95%; H, 6.64%; N, 17.9%.

EXAMPLE- 5 7-chloro-3-dimethylamino-(1,2-dihydro-1,2,4- benzotriazine) (M0 817) The compound of Formula II (X=7-Cl, Y=N(CH is used as starting material. It can be obtained from 3,7- dichloro 1,2,4-benzotriazine-l-oxide and dimethylamine in an alcoholic solution by heating to 80 C. under pressure (M.P. 133 C.). The aforesaid starting material is treated in alcoholic solution with hydrogen in the presence of Raney-nickel. The filtered solution containing the formed dihydro product is concentrated. After addition of concentrated alcoholic hydrochloric acid the product crystallizes in colorless needles of the hydrochloride. M.P. 215-220 C. (recrystallized from methanol).

Analysis.-C H Cl N (247.1). Calcd.: C, 43.75%; H, 4.89%; Cl, 28.69%. Found: C, 43.60%; H, 4.89%; Cl, 28.79%.

Addition of an excess of alcoholic hydrochloric acid and ether to the mother liquid yields a small amount of the dihydrochloride of 7-chloro-3-dimethylamino-1,2,3,4- tetrahydro-1,2,4-benzotriazine (M.P. 203-207 C.).

Analysis.C H Cl N (285.6). Calcd.: c, 37.85%; H, 5.3%; CI, 37.25%; N, 19.6%. Found: C, 38.22%; H, 5.38%; CI, 37.20%; N, 19.48%.

EXAMPLE 6 1,2- (n-butylmalonyl -3-ethoxy-7-chlorol,2-dihydro- 1,2,4-benzotriazine) (M0 813) The starting material of the Formula II (X=7 -Cl, Y=OC H5) M.P. 104.5 C. which can be obtained in a theoretical yield by reacting 3,7-dichloro-1,2,4-benzotriazine-l-oxide with sodium ethylate, is treated in alcoholic solution with catalytically activated hydrogen to give the dihydro-compound. After having evaporated the solution in vacuo, the residue is dissolved with benzene and the solution is dried over anhydrous CaSO To the dried solution are added 1 mol of butyl malonylchloride and 2 mols of triethylamine-both dissolved in abs. benzene. The rate of addition of the triethylamine should be somewhat greater than the rate of the acid chloride. After standing over night at room-temperature, precipitated triethylamine chlorhydrate is filtered off on a Biichnerfunnel. The product is extracted from the benzene-solution with diluted NaOH. After addition of a small excess of HCl to the alcalic solution, the product is extracted by methylene chloride. After evaporation of the solvent, a light-brown colored viscous oil is obtained. Having dissolved this oil in a small amount of alcohol, the product crystallizes in form of white needles. M.P. C.

Analysis.-C H ClN O (335.8). Calcd.: C, 57.23%; H, 5.4%; Cl, 10.56%; N, 12.51%. Found: C, 57.0%; H, 5.54%; Cl. 10.8%; N, 12.49%.

Example 7 1,2- (n-butylmalonyl) -7-chloro-3-propoxy- 1,2-dihydro- 1,2,4-benzotriazine) (M0 815) This product is obtained from 7-chloro-3-propoxy-1,2,4- benzotriazine 1 oxide (M.P. 131.5 C.) by the same method as described in Example 6. After crystallization from methanol the product melts at 107 C.

Analysis.C H ClN O (349.8). Calcd.: C; 58.35%; H, 5.76%; N, 12.01%. Found: C, 58.15%; H, 5.76%; N, 12.10%.

EXAMPLE 8 3 -ethylamin0-7-chloro- 1,2-dihydro-1,2,4-benzotriazine) (Mo 82 8 ether causes the product to crystallize as a hydrochloride,

which forms slightly colored needles. M.P. 193-195 C.

Analysis.C H N Cl (247.1). Calcd.: C, 45.98%; H, 5.40%; N, 21.49%. Found: C, 46.02%; H, 5.61%; N, 21.49%.

The free base can be liberated from the so obtained hydrochloride by treating its aqueous solution with sodium bicarbonate followed by extraction with methylene chloride.

By analogous methods there have been synthetisized the following derivatives of the 7-chloro-1,2-dihydro-1,2,4' benzotriazine substituted in the 3 position as hydrochlorides:

M.P., C. M0 823 the 3-piperidino derivative 203-207 M0 829 the 3-propylamino derivative 171-173 the 3-isobutylamino derivative 177-179 M0 849 the 3-(3-morpholino)-propyl derivative 223-225 M0 819 the 3-diethylamino derivative 205-209 M0 821 the 3-benzylamino derivative 180 M0 822 the 3-methylamino derivative 190-192 EXAMPLE 9 1-acetyl-3-dimethylamino-7-chloro-(1,2-dihydro- 1,2,4-benzotriazine) (M0 837) 3 dimethylarnino 7 chloro 1,2,4 benzotriazine 1- oxide (Formula II: X=7-Cl, Y=N(CH which has been used as starting material also in Example 5, is hydrogenated in the presence of Raney-nickel in 25 volume parts of ethanol containing 20% of acetic acid. After reduction the solvent is evaporated in vacuo, and the residue is dissolved in 10 vol. parts of glacial acetic acid. After addition of an equirnolar amount of acetic acid anhydride and a few drops of cone. H 50 the solution is refluxed for half an hour. After cooling, the reaction mixture is poured onto a mixture of crushed ice and an excess of cone. NaOH solution; the precipitated product is filtered on a Biichner-funnel. Recrystallized from methanol, the product forms lightly colored needles with a M.P. of 181- 183 C.

Analysis.C H ClN O (252.7). Calcd.: C, 52.29%; H, 5.18%; N, 22.17%. Found: C, 52.64%; H, 5.15%; N, 22.32%.

Reaction of the same starting material as above with 2 moles of acetic acid anhydride gives the diactyl derivative (M.P. 152 C.), with formic acid and 1 mole of acetic acid anhydride the l-formyl derivative (M.P. 179- 183" C.).

Treatment of the l-acetyl derivative with benzoyl chloride and triethylarnine yields the 1-acetyl-2-benzoyl derivative (M.P. 170-171 C.), replacement of benzoyl chloride by p-chlorobenzoyl chloride affords the corresponding l-acetyl-2-p-chlorobenzoyl derivative (M.P. 183- 184 C.). By analogous hydrogenation of 3-dimethylamino-7-methyl-1,2,4-benzotriazine 1 oxide followed by reaction with ethyl-chlorcarbonate the 1,2-di(ca1 bethoxy) 3 dimethylarnino 7 methyl (1,2 dihydro 1, 2,4-benzotriazine is obtained (M.P. 105 C.).

EXAMPLE 10 1,Z-butylmalonyl-3-dimethylamino-(1,2-dihydro-1,2,4-

benzotriazine) (M0 855) (a) In a 3-neck-flask with descending condenser to 3.8 g. of 3-dimethylarnino-(1,2-dihydro-1,2,4-benzotriazine are added 0.52 g. gmetallic sodium, dissolved in a small volume of abs. alcohol, 4.5 g. of diethylbutylmalonate and 15 ml. of xylene, in a nitrogen atmosphere. The mixture is heated during 2 hours to 70 C. then during 3 hours to 110-130 C. and during one more hour to 150 C. slowly distilling off the alcohol and most of the xylene. To the resulting lightly brown colored mass are added 200 ml. of water. The resulting solution is extracted twice with ether or benzene and afterwards acidified with HCl. Yield 3.6 g. of 1,2-butylmalonyl-3-dimethylarnino-( 1,2-dihydro 1,2,4 benzotriazine). After crystallisation from alcohol the melting point is 189- 190 C.

(b) 3 dimethylarnino 1,2,4 benzotriazine oxide (Formula II: X=H, Y=N(CH is shaken in the presence of Raney-nickel in 15 vol. parts of an alcoholacetic acid (9:1) mixture in a hydrogen-atmosphere. The mixture absorbs 2 moles hydrogen per 1 mol starting material. Hydrogenation can also be effected usingva palladiugm catalyst with a suitable solvent. After reduction it is filtered on a Biichner-funnel through a Hyflow-layer and the solvent is evaporated in vacuo under nitrogen. The residue is dissolved in 20- parts of water-free dioxane and treated at 60 C. with the calculated amount of butylmalonyl chloride (1 mol/mol) and triethylamine (2 mol/mol). The separated triethylamine hydrochloride is filtered, the dioxane-solution is evaporated under vacuo to dryness, and the residue is dissolved in 7 vol. parts of boiling acetic acid. After cooling, the product separates in lightly yellowish crystals. They are dissolved in the calculated amount of 0.25 N NaOH, treated with a small amount of carbon and precipitated with HCl. Melting point of the purified product is 187 C. Yield: approximately 60% of the theoretical amount.

Analysis.C H N O (300.4). Calcd.: C, 63.97%; H, 6.71%; N, 18.67%. Found: C, 64.08%; H, 7.87%; N, 18.79%.

By analogous methods the following derivatives of the 1,2 butylmalonyl 3 dimethylarnino (1,2 dihydro- 1,2,4-benzotriazine can be prepared:

M.P., C. M0 838 the 7-chloro derivative 202-203 M0 874 the 6-chloro derivative 203-205 Mi 57 the 7-methyl derivative 212-213 Mi 43 the 7-methoxy derivative 207 Mi 63 the 6,7-dimethyl derivative 216 Mi 42 the 6-methoxy-7-chloro derivative 206 Mi 73A the 6-dimethylamino-7-chloro derivative 117-118 In an analogous manner the following 1,2-alkylgmalonyl- 3 dimethylarnino (1,2 dihydro 1,2,4 benzotriazine) derivatives are obtained:

M.P., C. M0 884 the 1,2-(propylmalonyl) derivative 207 M0 886 the 1,2-(pentylmalonyl) derivative 188 Mo 887 the 1,2-(pentylmalonyl)-6-chloro derivative 200 M0 888 the 1,2-(propylmalonyl)-6-chloro derivative 195 M0 890 the 1,2-(cyclopentylmalonyl)-6-chloro derivative 191 Mi the 1,2-(propylmalonyl)-7-methyl derivative 228 Mi 88 the 1,2-(pentylmalonyl)-7-methyl derivative 215 EXAMPLE 11 1,2-butylmalonyl-3-phenyl-(1,2 dihydro-1,2,4- benzotriazine (Mo 889B) 10 g. of 3-phenyl-1,2,4-benzotriazine (prepared according to R. Fusco et al., 1st Lornb. r. sc. vol. 91, p. 936 (1957) CA. 53, 9243) are dissolved in a mixture of ethanol and acetic acid and treated with hydrogen in the presence of Raney-nickel. After hydrogenation the solvent is evaporated and the residue is dissolved in dioxane and in analogy to Example 10a treated with an equivalent amount of butylmalonyl-dichloride. After evaporation of the solvent, the reaction product is dissolved in dilute sodium hydroxide and precipitated with HCl. After recrystallisation from acetone colorless crystals are obtained with a melting point of -166 C.

We claim:

1. A method of alleviating inflamation, edema, pain, fever, and swelling of the joints comprising administering to the patient in need of such treatment an effective amount of a compound selected from the group consisting of compounds having the following formula and pharmaceutically acceptable salts thereof wherein X and X are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy and lower alkylarnino; Y is a member selected from the group consisting of amino, lower alkylamino, lower alkoxy, phenyl, piperidino, morpholino lower alkyl and phenyl lower alkyl; Z and Z when independent groups, are independently selected from the class consisting of hydrogen, acyl of lower aliphatic carboxyl acids, and acyl of araliphatic carboxylic acids; Z and Z when linked together, represent the diacyl di-radical of an acid selected from the group consisting of lower aliphatic dibasic carboxylic acids and lower aliphatic dibasic carboxylic acid whose alkylene group is substituted with cycloalkyl and when Y is amino, at least one of X X Z and Z is not hydrogen.

2. A method according to claim 1, wherein at least one of Z and Z is not hydrogen.

3. A method according to claim 2, wherein the compound is administered in a daily dosage of 50-1200 mg.

4. A method according to claim 1, wherein the compound is 3-ethylamino-7-chloro-1,2-dihydro-l,2,4-benzotriazine.

5. A method according to claim 1, wherein the compound is 1,2-propylmalonyl-3-diethylamino-6-chloro-1,2- dihydro-1,2,4-benzotriazine.

6. A method according to claim 1, wherein the compound is 1,2-propylmalonyl-El-dimethylamino-7-gnethyl- 1,2-dihydro-1,2,4-benzotriazine.

References Cited UNITED STATES PATENTS ALBERT T. MEYERS, Primary Examiner J. D. GOLDBERG, Assistant Examiner 

